Cardioprotection and altered mitochondrial adenine nucleotide transport

Steenbergen, Charles; Das, Samarjit; Su, Jason; Wong, Renee; Murphy, Elizabeth

doi:10.1007/s00395-009-0002-x

Cited by 29 publications

(19 citation statements)

References 45 publications

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“…7). We suggest that inhibition of RIP1-mediated necrosis not only reduces the initial loss of myocytes, but possibly leads to an increased resistance to oxidative stress, preventing additional I/R injury and spreading throughout the myocardium leading to less mitochondrial dysfunction [15,37]. This idea is supported by the fact that many mediators of I/R not only cause damage by themselves, but may also lead to a chain reaction of lethal injury and MPTP opening when ROS levels reach a certain threshold [52].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of RIP1-dependent necrosis prevents adverse cardiac remodeling after myocardial ischemia–reperfusion in vivo

et al. 2012

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Accumulating evidence indicates that programmed necrosis plays a critical role in cell death during ischemia-reperfusion. Necrostatin-1 (Nec-1), a small molecule capable of inhibiting a key regulator of programmed necrosis (RIP1), was shown to prevent necrotic cell death in experimental models including cardiac ischemia. However, no functional follow-up was performed and the action of Nec-1 remains unclear. Here, we studied whether Nec-1 inhibits RIP1-dependent necrosis and leads to long-term improvements after ischemia-reperfusion in vivo. Mice underwent 30 min of ischemia and received, 5 min before reperfusion, 3.3 mg/kg Nec-1 or vehicle treatment, followed by reperfusion. Nec-1 administration reduced infarct size to 26.3 ± 1.3% (P = 0.001) compared to 38.6 ± 1.7% in vehicle-treated animals. Furthermore, Nec-1 inhibited RIP1/RIP3 phosphorylation in vivo and significantly reduced necrotic cell death, while apoptotic cell death remained constant. By using MRI, cardiac dimensions and function were assessed before and 28 days after surgery. Nec-1-treated mice displayed less adverse remodeling (end-diastolic volume 63.5 ± 2.8 vs. 74.9 ± 2.8 μl, P = 0.031) and preserved cardiac performance (ejection fraction 45.81 ± 2.05 vs. 36.03 ± 2.37%, P = 0.016). Nec-1 treatment significantly reduced inflammatory influx, tumor necrosis factor-α mRNA levels and oxidative stress levels. Interestingly, this was accompanied by significant changes in the expression signature of oxidative stress genes. Administration of Nec-1 at the onset of reperfusion inhibits RIP1-dependent necrosis in vivo, leading to infarct size reduction and preservation of cardiac function. The cardioprotective effect of Nec-1 highlights the importance of necrotic cell death in the ischemic heart, thereby opening a new direction for therapy in patients with myocardial infarction.

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Section: Discussionmentioning

confidence: 99%

Inhibition of RIP1-dependent necrosis prevents adverse cardiac remodeling after myocardial ischemia–reperfusion in vivo

et al. 2012

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“…This preference for primed substrates provides a mean to integrate multiple signaling pathways within mitochondria. Although the role of GSK3β seems controversial, the majority of data suggests an important role for the phosphorylation of this enzyme in a cardioprotective scenario; for a review see [80].…”

Section: Discussionmentioning

confidence: 99%

“…[25, 68,[80][81][82][83]. Then ROS/RNS in turn lead to the activation of survival kinases such as MAP kinases, tyrosine kinases and PKCs, including PKCε and PKCδ, which may have opposing roles [12,15,16,31,36,45,58,62].…”

Section: It Is Known That I-postc Induces the Activation Of Reperfusimentioning

confidence: 99%

Diazoxide postconditioning induces mitochondrial protein S-Nitrosylation and a redox-sensitive mitochondrial phosphorylation/translocation of RISK elements: no role for SAFE

et al. 2013

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“…In this setting, VDAC acts as the critical gatekeeper for glycolytically-generated ATP to enter the IMS, where it is then transported by ANT into matrix to be consumed in this futile cycle. ATP and ADP can readily permeate the outer mitochondrial membrane when VDAC is in its open state, but are virtually impermeant when VDAC is closed [89]. It has been shown that HK binding promotes the closed state of VDAC, reducing the permeability to adenine nucleotides [90].…”

Section: Molecular Actions Of Hk That Impact Mptp Opening During I/rmentioning

confidence: 99%

Hexokinases and cardioprotection

Calmettes¹,

Ribalet²,

John³

et al. 2015

Journal of Molecular and Cellular Cardiology

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As mediators of the first enzymatic step in glucose metabolism, hexokinases (HKs) orchestrate a variety of catabolic and anabolic uses of glucose, regulate antioxidant power by generating NADPH for glutathione reduction, and modulate cell death processes by directly interacting with the voltage-dependent anion channel (VDAC), a regulatory component of the mitochondrial permeability transition pore (mPTP). Here we summarize the current state-of-knowledge about HKs and their role in protecting the heart from ischemia/reperfusion (I/R) injury, reviewing: 1) the properties of different HK isoforms and how their function is regulated by their subcellular localization; 2) how HKs modulate glucose metabolism and energy production during I/R; 3) the molecular mechanisms by which HKs influence mPTP opening and cellular injury during I/R; 4) how different metabolic and HK profiles correlate with susceptibility to I/R injury and cardioprotective efficacy in cancer cells, neonatal hearts, and normal, hypertrophied and failing adult hearts, and how these difference may guide novel therapeutic strategies to limit I/R injury in the heart.

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Cardioprotection and altered mitochondrial adenine nucleotide transport

Cited by 29 publications

References 45 publications

Inhibition of RIP1-dependent necrosis prevents adverse cardiac remodeling after myocardial ischemia–reperfusion in vivo

Inhibition of RIP1-dependent necrosis prevents adverse cardiac remodeling after myocardial ischemia–reperfusion in vivo

Diazoxide postconditioning induces mitochondrial protein S-Nitrosylation and a redox-sensitive mitochondrial phosphorylation/translocation of RISK elements: no role for SAFE

Hexokinases and cardioprotection

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